Ph I Dose Escalation Trial of Vandetanib in Combo w Etoposide for Malignant Gliomas

Sponsor

Annick Desjardins (Other)

Overall Status

Completed

CT.gov ID

NCT00613223

Collaborator

AstraZeneca (Industry)

Enrollment

Location

Arm

38.9

Duration (Months)

1.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Primary Objective: To determine maximum tolerated dose & dose limiting toxicity of vandetanib when combined with standard dosing of etoposide among patients with recurrent malignant glioma who are on & not on enzyme-inducing anti-epileptic drugs (EIAEDs) Secondary Objectives: To assess safety & tolerability of vandetanib + etoposide in this population; To evaluate pharmacokinetics of vandetanib among malignant glioma patients on & not on EIAEDs when combined with etoposide.

Exploratory Objective: To evaluate for evidence of anti-tumor activity of study regimen among recurrent malignant glioma patients including radiographic response rate, 6-month progression free survival (PFS) rate & median PFS.

Condition or Disease	Intervention/Treatment	Phase
Gliosarcoma Glioblastoma	Drug: Vandetanib and Etoposide	Phase 1

Detailed Description

This is open-label, single center, 2-cohort phase I dose-escalation study of vandetanib administered orally on continuous daily dosing schedule + oral etoposide among adult patients with recurrent or relapsing malignant glioma. Patients will be stratified based on whether they are receiving EIAEDs & each stratum will independently dose escalate. Dose of vandetanib will be increased in successive cohorts of patients. Etoposide will be given daily at a dose of 50mg/day for 21 days followed by 7 days with no etoposide. Cohorts of 3-6 subjects will accrue at each dose level until maximum tolerated dose (MTD) is defined. Subjects will be adult patients with histologically confirmed malignant glioma who are presenting at time of recurrence/relapse. Up to 48 subjects will be enrolled.

Sample size will be based on modified, classical "3+3" dose escalation design. Primary safety & efficacy analysis will be conducted on all subject data at time all subjects who are still receiving study drug will have completed at least 4 cycles of treatment. Most common adverse events (AEs) associated with vandetanib are rash, diarrhea, & asymptomatic QTc prolongation. Protracted oral dosing of etoposide is associated with toxicity that is mild in most patients & consists mainly of myelosuppression & diarrhea. Less commonly, protracted etoposide dosing has been associated w more significant hematologic toxicity.

Study Design

Study Type:

Interventional

Actual Enrollment :

49 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I Dose Escalation of Vandetanib (Zactima, ZD6474) in Combination With Etoposide for Malignant Gliomas

Study Start Date :

Feb 1, 2008

Actual Primary Completion Date :

Oct 1, 2010

Actual Study Completion Date :

May 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Vandetanib and Etoposide Patients will be stratified based on whether they are receiving an enzyme-inducing anti-epileptic drug (EIAED). The dose level of vandetanib will be increased in successive cohorts of subjects. Etoposide will be given daily at a dose of 50 mg/ day for 21 days followed by 7 days with no etoposide.	Drug: Vandetanib and Etoposide Vandetanib will be given orally once day. Swallow tablet with 240 ml of non-carbonated water. Initial dose is 100 mg/day for stratum 1 & 200 mg/day for stratum 2. Etoposide will be taken by mouth in capsule form at a flat dose of 50 mg/day for 1st 21 days of 28-day cycle. You will not take etoposide for following 7 days of the cycle. Other Names: Vandetanib - Zactima (ZD 6474) Etoposide - VP-16, Etopophos, Toposar, VePesid

Arm

Intervention/Treatment

Experimental: Vandetanib and Etoposide

Patients will be stratified based on whether they are receiving an enzyme-inducing anti-epileptic drug (EIAED). The dose level of vandetanib will be increased in successive cohorts of subjects. Etoposide will be given daily at a dose of 50 mg/ day for 21 days followed by 7 days with no etoposide.

Drug: Vandetanib and Etoposide

Vandetanib will be given orally once day. Swallow tablet with 240 ml of non-carbonated water. Initial dose is 100 mg/day for stratum 1 & 200 mg/day for stratum 2. Etoposide will be taken by mouth in capsule form at a flat dose of 50 mg/day for 1st 21 days of 28-day cycle. You will not take etoposide for following 7 days of the cycle.

Other Names:

Vandetanib - Zactima (ZD 6474)

Etoposide - VP-16, Etopophos, Toposar, VePesid

Outcome Measures

Primary Outcome Measures

Safety, tolerability, biologic activity, & pharmacokinetic profile of vandetanib when used in combo w etoposide [6-month progression free survival]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients have baseline evaluations ≤14days prior to 1st dose of study drug unless otherwise specified

Patients with confirmed malignant glioma (MG) who are recurrence/relapse
Patients may not have stereotactic tumor biopsy < 1 week or surgical resection or open biopsy < 4 weeks before starting study drug
For stratum of non-EIAED patients, each patient must be off all EIAEDs for > 2 weeks prior to starting study drug; similarly for stratum of EIAED patients, each patient must be on EIAED for >2 weeks prior to starting study drug
Patients should be on non-increasing dose of steroids for >7 days prior to obtaining baseline MRI with gadolinium (Gd-MRI) of brain
Patients should be on non-increasing dose of steroids for >7 days prior to starting study drug
Multifocal disease is eligible
Age ≥ 18 years
Karnofsky Performance Status (KPS) ≥70
Absolute Neutrophil Count ≥1.0 x 10 9/L
Hemoglobin (Hgb) ≥9 g/dL
Platelets ≥100 x 10 9/L
Serum creatinine ≤1.5 x ULRR or measured 24-hr CrCl ≥50mL/min/1.73m2
Life expectancy ≥ 12 weeks
Written informed consent obtained prior to screening procedures
Negative Beta-HCG pregnancy test for women of child-bearing potential

Exclusion Criteria:

Laboratory Results:
Serum direct bilirubin >1.5 x upper limit of normal (ULN) of reference range
Serum creatinine >1.5 x ULRR & CrCl <30 mL/min
Potassium, <4.0 mmol/L despite supplementation; serum calcium, magnesium out of normal range despite supplementation
ALT or AST > 2.5 x ULRR
Evidence of severe/uncontrolled systemic disease or any concurrent condition which in Investigator's opinion makes it undesirable for patient to participate in trial or which would jeopardize compliance with protocol
Clinically significant cardiovascular event such as myocardial infarction, superior vena cava syndrome, New York Heart Association classification of heart disease >2 within 3 months before entry; or presence of cardiac disease that, in opinion of Investigator, increases risk of ventricular arrhythmia
History of arrhythmia which is symptomatic/requires treatment/asymptomatic sustained ventricular tachycardia. Atrial fibrillation, controlled on medication is not excluded.
Previous history of QTc prolongation as result from other medication that required discontinuation of that medication
Congenital long QT syndrome, or 1st degree relative with unexplained sudden death <40 years
Presence of left bundle branch block
QTc with Bazett's correction that's unmeasureable, or ≥ 480msec on screening EEG.
Any concomitant medication that may cause QTc prolongation, induce Torsades de Pointes/induce CYP3A4 function except for EIAEDs
Hypertension not controlled by medical therapy
Currently active diarrhea that may affect ability of patient to absorb study regimen/tolerate diarrhea
Women who are currently pregnant/breast feeding
Previous or current malignancies of other histologies the last year, with exception of cervical carcinoma in situ & adequately treated basal cell or squamous cell carcinoma of skin
Receipt of any investigational agents <30 days prior to commencing study treatment unless pt has recovered from all anticipated toxicities of investigational agent
Last dose of prior chemo discontinued < 4 weeks before start of study therapy unless pt has recovered from all anticipated toxicities of chemo
Last XRT < 4 weeks before start of study therapy, unless patient has recovered from all anticipated toxicities of XRT
Any unresolved toxicity >CTC gr1 from previous anti-cancer therapy
Previous enrollment/randomization of treatment in present study
Major surgery < 4 weeks/incompletely healed surgical incision before starting study therapy
Patients who have received prior oral VEGFR, EGFR or PDGFR-directed therapies. Patients who received prior Avastin will be eligible as long as at least 6 weeks has elapsed since last dose.
Patients taking warfarin sodium